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Matthew Meyerson



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    IBS05 - Lung Cancer Genetics to Beat Lung Cancer (Ticketed Session) (ID 36)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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      IBS05.02 - Functional Genomic Approaches to Identify Novel Therapeutic Targets in Lung Cancer (Now Available) (ID 3329)

      07:00 - 08:00  |  Author(s): Matthew Meyerson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite the discovery and availability of targeted therapies and immunotherapies, lung cancer remains the leading cause of cancer death worldwide. Importantly, most lung cancer patients are not eligible for targeted therapies because their tumors lack an actionable genomic alteration. Moreover, immunotherapy-based regimens fail to induce treatment responses in a substantial proportion of lung cancer patients (1-3). Therefore, the identification of novel therapeutic modalities remains critical to improving outcomes in lung cancer care.

      Lung cancer cells may harbor specific genomic or functional alterations that render them vulnerable to particular genetic perturbations (4,5). Discovery of these synthetic lethal interactions may provide opportunities to develop novel classes of therapeutics for this disease. Through systematic analysis of genome-scale loss-of-function datasets (6,7), we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of lung cancer cell lines (8). ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Moreover, activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the cytoplasmic double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wild-type or catalytically inactive mutant version of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Taken together, these data nominate ADAR1 as a potential therapeutic target in lung cancers displaying elevated interferon-stimulated gene expression and underscore the ability of functional genomic approaches to uncover novel genetic vulnerabilities in lung cancer.

      References

      1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92

      2. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51

      3. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33

      4. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 2013;73:5508-18

      5. Zhou Z, Patel M, Ng N, Hsieh MH, Orth AP, Walker JR, et al. Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening. BMC Cancer 2014;14:944

      6. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell 2017;170:564-76 e16

      7. Aguirre AJ, Meyers RM, Weir BA, Vazquez F, Zhang CZ, Ben-David U, et al. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 2016;6:914-29

      8. Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, et al. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun 2018;9:5450

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    MS12 - Genome Screenings (ID 75)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Biology
    • Presentations: 1
    • Now Available
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      MS12.02 - Genomic and Functional Approaches to Understanding Cancer Aneuploidy (Now Available) (ID 3507)

      11:30 - 13:00  |  Author(s): Matthew Meyerson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Aneuploidy, whole chromosome or chromosome arm copy number imbalance, is a near-universal characteristic of human cancers. We applied methods that define chromosome arm-level aneuploidy and a global cancer aneuploidy score to 10,522 tumors of 33 types in the Cancer Genome Atlas (TCGA). Aneuploidy level was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high-aneuploidy samples.

      Although yeast and mammalian models of whole chromosome aneuploidies have been extensively investigated, chromosome arm-level aneuploidies have rarely been modeled. Cancer subtypes are often characterized by tumor specific patterns of these arm-level copy number alterations; for example, squamous cell carcinomas (SCCs) from different tissues of origin (including lung, esophagus, and bladder) have a pattern of chromosome 3p loss and chromosome 3q gain. Our analysis of 495 lung SCCs found chromosome 3p deletion to be the most frequent genomic alteration, occurring in almost 80% of the tumors and covering the entire length of the chromosome arm. Over two-thirds of chromosome 3p genes showed significantly decreased expression in these samples.

      Without models of chromosome arm-level alterations, the phenotypic effects of specific aneuploidies in cancer, such as 3p deletion, remain unknown. However, recent advances in genome engineering and targeting of endonucleases allow new approaches to generate chromosomal alterations. Here, we used the CRISPR-Cas9 system to delete one copy of chromosome 3p in vitro. We successfully isolated almost 90 clones of immortalized lung epithelial cells with deletion of the 3p arm, with 8 validated by whole genome sequencing. Consistent with patient data, expression of 3p genes was also decreased upon deletion, as well as increased expression of interferon response genes. Phenotypic characterization revealed that cells with chromosome 3p deletion initially proliferated more slowly than their siblings. These chromosome 3p deleted cells had increased G1 arrest, but did not undergo increased apoptosis or cell death. Interestingly, after several passages in culture, the proliferation defect was rescued in chromosome 3p deleted cells; genome sequencing and karyotype analyses suggested that this was the result of chromosome 3 duplication. With our cellular model of chromosome arm-level aneuploidy, we uncovered a possible selection mechanism that allows aneuploidy tolerance in vitro. We used genome engineering to model chromosome arm-level deletions, providing a robust model that will address a gap in our understanding of aneuploidy in cancer.

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